Association between family cancer history and risk of pancreatic cancer

PurposeFamily history of pancreatic adenocarcinoma is an established risk factor for the disease. However, associations of pancreatic cancer with other familial cancers are less clear. We analyzed data from the Queensland Pancreatic Cancer Study (QPCS), an Australian population-based case-control study, to investigate associations between family history of various cancer types and risk of pancreatic cancer.Materials and methodsOur study included 591 pancreatic cancer patients and 646 controls, all of whom self-reported the histories of cancer in their first-degree relatives. We used logistic regression to estimate adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Based on our results, we conducted a systematic literature review using the Medline (OVID) database to identify articles pertaining to the association between family history of melanoma and risk of pancreatic cancer. A meta-analysis including associations in five published studies, unpublished results from a study co-author and the QPCS results was then performed using the DerSimonian and Laird random-effects model.ResultsCases were more likely than controls to report a family history of pancreatic cancer (OR 2.20, 95% CI 1.16–4.19) and melanoma (OR 1.74, 95% CI 1.03–2.95), but not of breast, ovarian, respiratory, other gastrointestinal or prostate cancer. Meta-analysis of melanoma family history and pancreatic cancer risk yielded an OR of 1.22 (95% CI 1.00–1.51).ConclusionsOur results yield further evidence of increased risk of pancreatic cancer in those with family histories of the disease. We also provide suggestive evidence of an association between family history of melanoma and risk of pancreatic cancer.     

Endogenous estrogen, testosterone and progesterone levels in relation to breast cancer risk

Multiple lines of evidence support a central role of hormones in the etiology of breast cancer. In epidemiologic studies, considerable effort has focused on delineating the role of endogenous hormones in risk of breast cancer among postmenopausal women. Recently, substantial additional data has accrued from prospective studies where endogenous hormones are measured in study subjects prior to disease diagnosis. In this review, the epidemiologic evidence linking sex steroids—estrogens, testosterone, and progesterone, specifically—with subsequent risk of breast cancer in both premenopausal and postmenopausal women is summarized. Overall, a strong positive association between breast cancer risk and circulating levels of both estrogens and testosterone has now been well confirmed among postmenopausal women; women with hormone levels in the top 20% of the distribution (versus bottom 20%) have a two- to three-fold higher risk of breast cancer. Evidence among premenopausal women is more limited, though increased risk associated with higher levels of testosterone is consistent. However, both positive and null associations have been observed with estrogens and progesterone and clearly more evaluation is needed.     

Reproductive factors and breast cancer risk in Palestine: A case control study

BackgroundEarly age at menarche, late age at menopause, and late age at first full-term pregnancy are linked to a modest increase in the risk of developing breast cancer (breast ca). This study aims to investigate the reproductive determinants of breast cancer among women in the West Bank of Palestine.A structured questionnaire was used to collect data in a case-control study (237 registered cases and 237 controls). A multivariate analysis model was used to adjust for the association between women’s reproductive factors and breast ca risk. This study was approved by Al Quds University Ethical Research Committee and the Ministry of Health research unit.ResultsIn the multivariate analysis, menarche after 13 years of age, use of oral contraceptives for more than two months, and hormonal contraceptives use significantly doubled the risk for breast ca (Adjusted Odds Ratio (AOR) = 2.03, 95 % CI: 1.21–4.37, p < 0.011 and AOR = 2.2, 95 % CI: 1.24–4.01, p = 0.008, respectively). Women who used hormone replacement therapy (HRT) were significantly associated with higher odds (5 folds) of having breast ca versus those who did not use them (AOR 5.02, 95 % CI: 1.93–13.06, p = 0.001). Similarly, nulliparous women showed 6 times the odds of breast ca compared with women with one or more children (p = 0.005). Also, parental consanguinity marriage (AOR 2.59, 95 % CI: 1.53–4.36, p = 0.001) and positive family history (AOR 3.88, 95 % CI: 2.19–6.87, p = 0.001) of the condition can be strong determinants for breast ca in this study.ConclusionThis study provides clear evidence that the use of reproductive hormones, whether as a birth control tool or for therapeutic purposes, must be rationalized worldwide and in Palestine in particular.     

Risk stratification of women with false-positive test results in mammography screening based on mammographic morphology and density: A case control study

BackgroundThe long-term risk of breast cancer is increased in women with false-positive (FP) mammography screening results. We investigated whether mammographic morphology and/or density can be used to stratify these women according to their risk of future breast cancerMethodsWe undertook a case-control study nested in the population-based screening programme in Copenhagen, Denmark. We included 288 cases and 288 controls based on a cohort of 4743 women with at least one FP-test result in 1991–2005 who were followed up until 17 April 2008. Film-based mammograms were assessed using the Breast Imaging-Reporting and Data System (BI-RADS) density classification, the Tabár classification, and two automated techniques quantifying percentage mammographic density (PMD) and mammographic texture (MTR), respectively. The association with breast cancer was estimated using binary logistic regression calculating Odds Ratios (ORs) and the area under the receiver operating characteristic (ROC) curves (AUCs) adjusted for birth year and age and invitation round at the FP-screenResultsSignificantly increased ORs were seen for BI-RADS D(density)2-D4 (OR 1.94; 1.30-2.91, 2.36; 1.51-3.70 and 4.01; 1.67-9.62, respectively), Tabár’s P(pattern)IV (OR 1.83; 1.16-2.89), PMD Q(quartile)2-Q4 (OR 1.71; 1.02-2.88, 1.97; 1.16-3.35 and 2.43; 1.41-4.19, respectively) and MTR Q4 (1.97; 1.12-3.46) using the lowest/fattiest category as referenceConclusionAll four methods, capturing either mammographic morphology or density, could segregate women with FP-screening results according to their risk of future breast cancer − using already available screening mammograms. Our findings need validation on digital mammograms, but may inform potential future risk stratification and tailored screening strategies     

Active cigarette smoking and the risk of breast cancer: a cohort study

BackgroundTobacco use has been implicated in the etiology of a large number of cancers, and there exists substantial biological plausibility that it could also be involved in breast carcinogenesis. Despite this, epidemiological evidence to date is inconsistent. The aim of this study was to investigate the role of active smoking and the risk of incident, invasive breast cancer using a prospective cohort of women from the Canadian Study of Diet, Lifestyle and Health.MethodsUsing a case-cohort design, an age-stratified subcohort of 3314 women was created from 39,532 female participants who returned completed self-administered lifestyle and dietary questionnaires at baseline. A total of 1096 breast cancer cases were identified in the entire cohort (including 141 cases from the subcohort) by linkage to the Canadian Cancer Registry. Cox regression models were used to estimate hazard ratios for the association between the different smoking exposures and the risk of breast cancer, using a modification for the case-cohort design.ResultsAfter carefully considering early-life exposures and potential confounders, we found no association between any smoking exposure and risk of breast cancer in this study (Hazard ratio = 1.00, 95% confidence interval = 0.87–1.17 for ever vs never smokers).ConclusionsAlthough these results cannot rule out an association between smoking and breast cancer, they do agree with the current literature suggesting that, if an association does exist, it is relatively weak.     

Pregnancy, progesterone and progestins in relation to breast cancer risk

In the last two decades the prevailing opinion, supported by the “estrogen augmented by progesterone” hypothesis, has been that progesterone contributes to the development of breast cancer (BC). Support for this opinion was provided by the finding that some synthetic progestins, when added to estrogen in hormone replacement therapy (HRT) for menopausal complaints, increase the BC risk more than estrogen alone. However, recent findings suggest that both the production of progesterone during pregnancy and the progesterone endogenously produced or exogenously administered outside pregnancy, does not increase BC risk, and could even be protective. The increased BC risk found with the addition of synthetic progestins to estrogen in HRT seems in all likehood due to the fact that these progestins (medroxyprogesterone acetate and 19-nortestosterone-derivatives) are endowed with some non-progesterone-like effects which can potentiate the proliferative action of estrogens. The use of progestational agents in pregnancy, for example to prevent preterm birth, does not cause concern in relation to BC risk.     

Socioeconomic position and lifestyle in relation to breast cancer incidence among postmenopausal women: a prospective cohort study, Denmark, 1993-2006

Background: In Denmark, the incidence of breast cancer is higher among women with higher socioeconomic position. We investigated whether differences in exposure to certain risk factors contribute to this gradient, as measured from education, income and occupation. Methods: We conducted a cohort study of 23 111 postmenopausal women aged 50–65 years who were enrolled in the prospective Danish ‘Diet, Cancer and Health’ study between 1993 and 1995. At baseline, all women filled in a questionnaire on lifestyle and food frequency. The results were analysed in Cox proportional hazard models. Results: Part of the association with socioeconomic position is due to the potential mediators reproductive pattern, use of hormone replacement therapy and alcohol consumption. After simultaneous adjustment for these factors, the hazard ratios were 1.06 (95% confidence interval [CI], 0.88–1.27) for women with higher education and 1.07 (95% CI, 0.85–1.34) for women with higher income. The HR ratio for women working as higher officials when compared with unskilled workers was 1.23 (0.96–1.59). Conclusion: The results support the hypothesis that the higher incidence of breast cancer among socially advantaged women is mediated partly by differences in exposure to reproductive factors, hormone replacement therapy and alcohol.     

Allergic diseases and asthma in the family predict the persistence and onset-age of asthma: a prospective cohort study

BackgroundFamily history of asthma and other allergic diseases have been linked to the risk of childhood asthma previously, but little is known about their effect on the age-of-onset and persistency of asthma until young adulthood.MethodsWe assessed the effect of the family history of asthma and allergic diseases on persistent vs. transient, and early- vs. late-onset persistent asthma in The Espoo Cohort Study 1991–2011, a population-based cohort study of 1623 subjects (follow-up rate 63.2%). The determinants were any family history (any parent or sibling); maternal; paternal; siblings only; parents only; and both siblings and parents. Analyses were conducted separately for asthma and allergic diseases while taking the other disease into account as a confounding factor. The outcomes were persistent, transient, early-onset persistent (<13 years) and late-onset persistent asthma. Adjusted risk ratios (RR) were calculated applying Poisson regression. Q-statistics were used to assess heterogeneity between RRs.ResultsFamily history was associated with the different subtypes but the magnitude of effect varied quantitatively. Any family history of asthma was a stronger determinant of persistent (adjusted RR = 2.82, 95% CI 1.99-4.00) than transient asthma (1.65, 1.03-2.65) (heterogeneity: P = 0.07) and on early-onset than late-onset persistent asthma. Also any family history of allergic diseases was a stronger determinant of persistent and early-onset asthma. The impact of paternal asthma continued to young adulthood (early-onset: 3.33, 1.57-7.06 vs. late-onset 2.04, 0.75-5.52) while the influence of maternal asthma decreased with age (Early-onset 3.94, 2.11-7.36 vs. Late-onset 0.88, 0.28-2.81). Paternal allergic diseases did not follow the pattern of paternal asthma, since they showed no association with late-onset asthma. Also the effect estimates for other subtypes were lower than in other hereditary groups (persistent 1.29, 0.75-2.22 vs. transient 1.20, 0.67-2.15 and early-onset 1.86, 0.95-3.64 vs. late-onset 0.64, 0.22-1.80).ConclusionsFamily history of asthma and allergic diseases are strong determinants of asthma, but the magnitude of effect varies according to the hereditary group so that some subtypes have a stronger hereditary component, and others may be more strongly related to environmental exposures. Our results provide useful information for assessing the prognosis of asthma based on a thorough family history.     

Breast cancer family history and allele-specific DNA methylation in the legacy girls study

Family history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6–13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (Δ4.9%, P = 0.003) and SEC16B (Δ3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter-individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences.     

Risk factors for breast cancer in the breast cancer risk model study of Guam and Saipan

BackgroundChamorro Pacific Islanders in the Mariana Islands have breast cancer incidence rates similar to, but mortality rates higher than, those of U.S. women. As breast cancer risk factors of women of the Mariana Islands may be unique because of ethnic and cultural differences, we studied established and suspected risk factors for breast cancer in this unstudied population.MethodsFrom 2010–2013, we conducted retrospective case-control study of female breast cancer (104 cases and 185 controls) among women in the Mariana Islands. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each of various lifestyle-related factors from logistic regression of breast cancer, in all women and in pre- and postmenopausal women separately. Tests for interaction of risk factors with ethnicity were based on the Wald statistics for cross-product terms.ResultsOf the medical and reproductive factors considered — age at menarche, breastfeeding, number of live births, age at first live birth, hormone use, and menopause — only age at first live birth was confirmed. Age at first live birth, among parous women, was higher among cases (mean 24.9 years) than controls (mean 23.2 years); with increased breast cancer risk (OR = 2.53; 95% CI, 1.04–6.19 for age ≥ 30y compared to <20y, P for trend = 0.01). Of the lifestyle factors —body mass index, waist circumference, physical activity, alcohol and betel-nut intake, and education — only waist circumference (OR = 1.65; 95% CI 0.87–3.14 for the highest tertile group compared to the lowest, P for trend = 0.04) was significantly associated with breast cancer risk and only in Filipino women. The association with many other established risk factors, such as BMI, hormone use and physical activity, were in the expected direction but were not significant. Associations for family history of breast cancer and alcohol intake were not evidentConclusionsThe results provide a basis for cancer prevention guidance for women in the Mariana Islands.     

Referent sampling,family history and relative risk: the role of length-biased sampling

Familial risk of disease is often assessed using case control studies based on referent databases. A referent database is a collection of family histories of cases typically assembled as a result of one family member being diagnosed with disease. This sampling scheme is equivalent to sampling families proportional to their size. The larger the family, the greater the probability of finding the family in the referent registry. This phenomena is known as length-biased sampling. The consequence of this kind of sampling is to bias the regression estimate associated with family history. The estimate is typically inflated in comparison to what is true for the actual population.     

Low-dose aspirin use and survival in breast cancer patients: A nationwide cohort study

BackgroundPreclinical evidence from breast cancer cell lines and animal models suggest that aspirin could have anti-cancer properties. In a large breast cancer patient cohort, we investigated whether post-diagnostic low-dose aspirin use was associated with a reduction in the risk of breast cancer-specific mortality.MethodsWe identified 15,140 newly diagnosed breast cancer patients within the Scottish Cancer Registry. Linkages to the Scottish Prescribing Information System provided data on dispensed medications and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Time-dependent Cox regression models were used to calculate hazard ratios (HR) and 95% CIs for breast cancer-specific and all-cause mortality by post-diagnostic low-dose aspirin use. HRs were adjusted for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of statins. Secondary analysis investigated the association between pre-diagnostic low-dose aspirin use and breast cancer-specific and all-cause mortality.ResultsPost-diagnostic users of low-dose aspirin appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.44, 95% CI 1.26, 1.65) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.92, 95% CI 0.75, 1.14). Findings were similar in analysis by increasing duration of use and in analysis of pre-diagnostic low-dose aspirin use.ConclusionIn this large nationwide study of breast cancer patients, we found little evidence of an association between post-diagnostic low-dose aspirin use and cancer-specific mortality.     

Differences in DNA methylation by extent of breast cancer family history in unaffected women

Breast cancer clusters within families but genetic factors identified to date explain only a portion of this clustering. Lower global DNA methylation in white blood cells (WBC) has been associated with increased breast cancer risk. We examined whether WBC DNA methylation varies by extent of breast cancer family history in unaffected women from high-risk breast cancer families. We evaluated DNA methylation levels in LINE-1, Alu and Sat2 in 333 cancer-free female family members of the New York site of the Breast Cancer Family Registry, the minority of which were known BRCA1 or BRCA2 mutation carriers. We used generalized estimated equation models to test for differences in DNA methylation levels by extent of their breast cancer family history after adjusting for age. All unaffected women had at least one sister affected with breast cancer. LINE-1 and Sat2 DNA methylation levels were lower in individuals with 3 or more (3+) first-degree relatives with breast cancer relative to women with only one first-degree relative. For LINE-1, Alu, and Sat2, having 3+ affected first-degree relatives was associated with a decrease of 23.4% (95%CI = ?46.8%, 0.1%), 17.9% (95%CI = ?39.5%, 3.7%) and 11.4% (95% CI = ?20.3%, ?2.5%), respectively, relative to individuals with only one affected first-degree relative, but the results were only statistically significant for Sat2. Individuals having an affected mother had 17.9% lower LINE-1 DNA methylation levels (95% CI = ?28.8%, ?7.1%) when compared with those not having an affected mother. No associations were observed for Alu or Sat2 by maternal breast cancer status. If replicated, these results indicate that lower global WBC DNA methylation levels in families with extensive cancer histories may be one explanation for the clustering of cancers in these families. Family clustering of disease may reflect epigenetic as well as genetic and shared environmental factors.     

Differences in DNA methylation by extent of breast cancer family history in unaffected women

Breast cancer clusters within families but genetic factors identified to date explain only a portion of this clustering. Lower global DNA methylation in white blood cells (WBC) has been associated with increased breast cancer risk. We examined whether WBC DNA methylation varies by extent of breast cancer family history in unaffected women from high-risk breast cancer families. We evaluated DNA methylation levels in LINE-1, Alu and Sat2 in 333 cancer-free female family members of the New York site of the Breast Cancer Family Registry, the minority of which were known BRCA1 or BRCA2 mutation carriers. We used generalized estimated equation models to test for differences in DNA methylation levels by extent of their breast cancer family history after adjusting for age. All unaffected women had at least one sister affected with breast cancer. LINE-1 and Sat2 DNA methylation levels were lower in individuals with 3 or more (3+) first-degree relatives with breast cancer relative to women with only one first-degree relative. For LINE-1, Alu, and Sat2, having 3+ affected first-degree relatives was associated with a decrease of 23.4% (95%CI = −46.8%, 0.1%), 17.9% (95%CI = −39.5%, 3.7%) and 11.4% (95% CI = −20.3%, −2.5%), respectively, relative to individuals with only one affected first-degree relative, but the results were only statistically significant for Sat2. Individuals having an affected mother had 17.9% lower LINE-1 DNA methylation levels (95% CI = −28.8%, −7.1%) when compared with those not having an affected mother. No associations were observed for Alu or Sat2 by maternal breast cancer status. If replicated, these results indicate that lower global WBC DNA methylation levels in families with extensive cancer histories may be one explanation for the clustering of cancers in these families. Family clustering of disease may reflect epigenetic as well as genetic and shared environmental factors.     

Effect of body-mass index on the risk of gastric cancer: A population-based cohort study in A Japanese population

BackgroundBody fatness and weight gain are considered probable causes of gastric cancer, specifically in the cardia region. However, limited evidence is available in Asia, where the burden of gastric cancer is high. The objective of this study was to determine an association between body-mass index (BMI) and gastric cancer risk using a large population prospective cohort.Methods92,056 subjects enrolled in the Japan Public Health Center-based prospective Study who reported their height and weight were followed up until the end of 2013. A Cox proportional hazards model was used to estimate the risk for gastric cancer and its subsite based on baseline BMI. A subgroup analysis was conducted taking account of Helicobacter pylori (H. pylori) infection and atrophic gastritis status.Results2,860 gastric cancer cases (2,047 men, 813 women), 307 proximal gastric cancer cases (244 men, 63 women), and 1967 distal gastric cancer cases (1,405 men, 562 women) were found during the follow-up period. Among men, baseline BMI ≥ 27 kg/m² increased the risk of overall gastric cancer (hazards ratio (HR) 1.23, 95% confidence interval (CI) 1.00–1.53). For both sexes, U-shaped increase in the risk was observed for proximal gastric cancer. Subgroup analysis showed a statistically significant association between the risk of proximal gastric cancer and BMI ≥ 27 kg/m² among those who were atrophic gastritis positive, H. pylori antibody positive, and those who tested positive to either or both atrophic gastritis and H. pylori antibody.ConclusionOur result suggests that gastric cancer risk increases for men with BMI ≥ 27 kg/m².     

Estrogen receptor β in the breast: role in estrogen responsiveness and development of breast cancer

Breast cancer is one of the most common forms of cancer observed in women. Endogenous estrogen is thought to play a major role in its development and estrogen receptor blockers are the most important drugs in its treatment. It has long been thought that any conditions or exposures, which enhance estrogenic responses, would result in an increased risk for breast cancer. The discovery of the second estrogen receptor, ERβ, which can have effects opposite to those of the well-known ‘original’ estrogen receptor (now called ER) challenges this simplistic view. In order to understand breast cancer one must first understand how the normal breast is maintained. The functions of ERβ in the breast remain to be defined but from what we have learnt about its activities in in vitro systems, this estrogen receptor may have a protective role in the breast. Studies in human and rodent breasts as well as in human breast cancer biopsies reveal that ERβ is by far the more abundant of the two ERs. Despite the role of estrogen in proliferation of the breast, neither of the two ERs appears to located in epithelial cells which divide in response to estrogen. In order to define the functions of ERβ in the normal and malignant breast, we have created mice in which the ERβ gene has been inactivated. Studies of the breasts of ERβ knock out mice (BERKO) revealed abnormal epithelial growth, overexpression of Ki67 and severe cystic breast disease as mice age.     

Type 2 diabetes,obesity, and breast cancer risk among Japanese women of the atomic bomb survivor cohort

BackgroundMuch less is known about diabetes than obesity as a predictor of breast cancer incidence and most previous studies have been conducted in white populations. Therefore, this project within the Radiation Effects Research Foundation’s cohort of Japanese atomic bomb survivors aimed to determine the independent contributions of obesity and diabetes to develop breast cancer.MethodsAfter excluding women with unknown A-bomb radiation dose, a radiation dose of ≥100 mGy, a pre-existing history of breast cancer, and missing body mass index (BMI), the analysis included 29,818 women. Breast cancer status and deaths until 2009 were identified from cancer registries and vital records. Cox regression with age as the time metric was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BMI and diabetes status as time-varying exposures alone and in combination while adjusting for known confounders.ResultsDiabetes prevalence increased from 2.6% to 5.3% and 7.5% from the first to the second and third data collection. During 27.6 ± 12.2 years of follow-up, 703 women had developed breast cancer (mean age of 66.0 ± 12.9 years) and 31 (4.4%) had been diagnosed with diabetes. A diagnosis of diabetes was not significantly associated with breast cancer incidence without (HR 1.12, 95% CI 0.77–1.64) and with BMI (HR 1.01, 95% CI 0.69–1.49) as a covariate. The respective HRs for overweight and obesity were 1.61 (95% CI 1.34–1.93) and 2.04 (95% CI 1.40–2.97).ConclusionsAmong a long-time Japanese cohort, excess body weight but not a diabetes diagnosis was significantly associated with breast cancer risk.     

Diagnostic and prognostic value of miR-200 family in breast cancer: A meta-analysis and systematic review

BackgroundBreast cancer (BC) is the most common cancer for women all over the world. Great interests have been paid to discover accurate and noninvasive methods for breast cancer diagnosis and prognosis. Although the diagnostic and prognostic value of microRNA-200 (miRNA- 200, miR-200) family has been revealed in many studies, the results were inconsistent. Thus, this meta-analysis aims to assess the overall value of miRNA-200 family in breast cancer diagnosis and prognosis.MethodRelevant studies were searched from the following databases: PubMed, PMC, EMBASE, and ScienceDirect using key words: ("miRNA-200 family" or "miR-141" or "miR-200a" or "miR-200b" or "miR-200c" or "miR-429") and (“HER2” or “Luminal A” or “Luminal B” or “TNBC”) and ("breast cancers" or "breast carcinoma" or "breast malignancy" or "breast tumor"). The sensitivity, specificity, AUC were then calculated to estimate the diagnostic accuracy of the miR-200 family. As for the prognostic value of the miR-200 family, the pooled hazard ratio (HR) was assessed. Heterogeneity among individual studies was also examined by subgroup analyses.ResultA total of 24 articles were included in the meta-analysis. The diagnostic value of miR-200s in BC was presented by the pooled sensitivity was 0.86 (95% CI: 0.83-0.88); the pooled specificity was 0.82 (95% CI: 0.72-0.89); the pooled AUC was 0.931 (95% CI: 0.919-0.942). Besides, expression of miR-200s in metastatic breast cancer has sensitivity, specificity and AUC of 0.70 (95%CI: 0.56-0.81), 0.72 (95%CI: 0.61-0.81), and 0.814 (95%CI: 0.741-0.903), respectively. The meta-analysis then revealed that high expression of miR-200 family corresponded to poor OS (HR: 1.63, 95% CI: 1.03-2.52), poor DFS (HR: 1.55, 95% CI: 0.95-2.56) in BC patients while downregulation of miRNA-200s corresponded to poor OS (HR= 0.84, 95%CI: 0.46-1.63) in TNBC patients and poor OS (HR=0.49; 95%CI: 0.27-0.88) in luminal BC patient.ConclusionThe MiR-200 family has high diagnostic accuracy and can be used as an important biomarker to prognosticate breast cancer.     

pSTAT3和SOCS3在人乳腺癌组织中的表达及意义

目的 研究激活STAT3( pSTAT3)蛋白和SOCS3在人乳腺癌和乳腺良性病变组织中的蛋白表达及其临床意义.方法 应用免疫组织化学检测160例乳腺癌和36例乳腺良性病变组织pSTAT3和SOCS3蛋白的表达情况,分析它们与患者临床病理特征的关系.结果 人乳腺癌组织中pSTAT3和SOCS3蛋白表达阳性率分别为69.4％和40.0％,乳腺良性病变组织中pSTAT3和SOCS3蛋白表达阳性率分别为33.3％和22.2％,前者与后者相比具有统计学意义(P＜0.01和P＜0.05);乳腺癌pSTAT3蛋白表达与肿瘤的大小、淋巴结转移和临床分期均呈显著正相关(均P＜0.01),但与患者年龄、肿瘤的组织学分级、雌孕激素受体表达和c-erBb-2表达均无显著相关(均P＞0.05);SOCS3蛋白表达与肿瘤大小呈显著正相关(P＜0.05),但与患者年龄、淋巴结转移、临床分期、肿瘤的组织学分级、雌孕激素受体表达和c-erBb-2表达均无显著相关(均P＞0.05);乳腺癌pSTAT3和SOCS3表达呈显著正相关(r=0.237,P＜0.01).结论 乳腺癌pSTAT3和SOCS3表达状况与肿瘤生长、侵袭和转移等呈密切相关,提示STAT3和SOCS3可能在乳腺癌发生发展过程中发挥了重要作用.     

The HER2 amplicon in breast cancer: Topoisomerase IIA and beyond

HER2 gene amplification is observed in about 15% of breast cancers. The subgroup of HER2-positive breast cancers appears to be heterogeneous and presents complex patterns of gene amplification at the locus on chromosome 17q12-21. The molecular variations within the chromosome 17q amplicon and their clinical implications remain largely unknown. Besides the well-known TOP2A gene encoding Topoisomerase IIA, other genes might also be amplified and could play functional roles in breast cancer development and progression. This review will focus on the current knowledge concerning the HER2 amplicon heterogeneity, its clinical and biological impact and the pitfalls associated with the evaluation of gene amplifications at this locus, with particular attention to TOP2A and the link between TOP2A and anthracycline benefit. In addition it will discuss the clinical and biological implications of the amplification of ten other genes at this locus (MED1, STARD3, GRB7, THRA, RARA, IGFPB4, CCR7, KRT20, KRT19 and GAST) in breast cancer.